African American men have two times or more the incidence rate of prostate cancer than other U.S. populations, and high rates of prostate cancer are also seen in other African and African-derived populations. It is generally accepted that both common and rare genetic variants contribute to risk of complex diseases such as prostate cancer, however their relative contributions to overall heritability is a subject of intense controversy. For rare variants to have a significant influence on the risk of complex disease the spectrum of effect sizes must be considerably larger in magnitude than for common variants; to date however there is only limited evidence for or against this hypothesis since the means of comprehensively testing rare variation in the genome has not been possible until very recently. In this proposal we seek to test the contributions of both common and rare genetic variants to the risk of prostate cancer in men of American ancestry using a targeted genome-wide association study approach. In Aim 1 we plan to sequence (at 30x coverage) the exome and regulatory regions (~160 Mb) of the genome, as defined by epigenetic marks in prostate cancer cell lines, in 1,000 men of African ancestry (500 with aggressive disease) and 1,000 controls. Both single SNP and burden of rare variants analyses will be performed and replication testing of the most statistically significant sequence variations (~24,000) will be examined in additional samples of African ancestry (6,000 cases and 6,000 controls) through the African Ancestry Prostate Cancer (AAPC) consortium. In addition to association testing of single variants, we will conduct burden of rare variants analyses of coding and non-coding variants at the gene and pathway level. In Aim 2, we will examine interactions between associated variants, environmental factors (thereby better defining the role of these factors) and disease severity. In Aim 3, we will assess biological function of the novel risk alleles identified in Aim 1 using a staged approach of eQTL analysis followed by in vitro analyses of enhancer activity as well as allele-specific effects. This proposal spans the spectrum of genetic epidemiologic research in prostate cancer, from genetic discovery (for all prostate cancer as well as aggressive disease) to gene environment interaction testing, to biological understanding. We expect this work to significantly advance knowledge of the etiology of prostate cancer and racial/ethnic disparities in prostate cancer risk, and to guide the development of future preventive, early detection, prognostic and even therapeutic measures.